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No Apparent Requirement for Neuronal Sodium Channels in Excitation-Contraction Coupling in Rat Ventricular Myocytes

From the Department of Physiology, University of Bristol, United Kingdom.

Correspondence to Fabien Brette, University of Manchester, Faculty of Life Sciences, 2.18A Core Technology Facility, 46 Grafton Street, Manchester, M13 9NT, United Kingdom. E-mail f.brette{at}manchester.ac.uk

The majority of Na channels in the heart are composed of the tetrodotoxin (TTX)-resistant (K_D, 2 to 6 µmol/L) "cardiac" Na_V1.5 isoform; however, TTX-sensitive (K_D, 1 to 25 nmol/L) "neuronal" Na channel isoforms have recently been detected in several cardiac preparations. In the present study, we determined the functional subcellular localization of Na channel isoforms (according to their TTX sensitivity) in rat ventricular myocytes by recording I_Na in control and detubulated myocytes. We found that TTX-sensitive I_Na (K_D, &8.8 nmol/L) makes up 14±3% of total I_Na in control and 4% in detubulated myocytes and calculated that &80% of TTX-sensitive I_Na is located in the t-tubules, where it generates &1/3 of t-tubular I_Na. In contrast, TTX-resistant I_Na is located predominantly (&78%) at the surface membrane. We also investigated the possible contribution of TTX-sensitive I_Na to excitation-contraction coupling, using 200 nmol/L TTX to selectively block TTX-sensitive I_Na. TTX decreased the rate of depolarization of the action potential by 10% but did not delay the rise of systolic Ca²⁺ in the center of the cell (transverse confocal line scan), suggesting that TTX-sensitive I_Na does not play a role in synchronizing Ca²⁺ release at the t-tubules; the amplitude of the Ca²⁺ transient and contraction were also unchanged by 200 nmol/L TTX. The quantity of charge entering via I_Ca elicited by control or TTX action potential waveforms was similar, suggesting that the trigger for Ca²⁺ release is not altered by blocking TTX-sensitive I_Na. We conclude that neuronal I_Na is concentrated at the t-tubules, but there is no evidence of a requirement for these channels in normal excitation-contraction coupling in ventricular myocytes.

Key Words: cardiac myocytes • sodium channels • excitation-contraction coupling • electrophysiology

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